All controlled release pharmaceutical products have in common the goal of improving drug therapy over that achieved with their non-controlled counterparts. Ideally, the use of an optimally designed controlled release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
In general, a controlled release preparation is a pharmaceutical composition capable of releasing the active substance at the required rate to maintain a constant pharmacological activity for some desirable period of time. Such dosage forms provide a supply of a drug to the body during a predetermined period of time and thus maintain drug levels in the therapeutic range for longer periods of time than conventional non-controlled formulations.
Drug levels can be maintained in the therapeutic range for longer periods of time by giving larger doses of conventionally formulated dosage forms. However, this is not usually a suitable approach, as such doses may produce toxic drug levels. Alternatively, another approach is to administer a drug at frequent intervals of time, resulting in oscillating drug levels, the so-called peak and valley effect. This approach is generally associated with several potential problems, such as a large peak (toxic effect) and valley (non-active drug level) effect, and a lack of patient compliance leading to drug therapy inefficiency or failure.
Controlled release preparations may be designed to rapidly release a predetermined fraction of the total drug dose. This loading dose is an amount of a drug which will provide a desired pharmacological response as promptly as is possible according to the biopharmaceutical properties of the drug. Such formulations which initially release a burst of a therapeutic agent and then release the agent at an essentially constant rate are known e.g. from EP Patent Application No. 103,387. EP Patent Application No. 117.164 and U.S. Pat. No 4.576,604.
The above-mentioned controlled release preparations are long-acting and release the drug in a sustained manner. However, these types of formulations may result in an undesirable decreased bioavailability, and furthermore, the maintenance of the therapeutic drug level in an organism for a prolonged period of time may lead to the development of tolerance and chronic toxicity.
In the case of sustained release or long-acting preparations, the active substance is continuously and slowly released from the preparation at a constant and controlled rate. However, it is impossible to interrupt the release of active substance from such preparations, i.e. to release it at timed intervals.
It has, however, recently been accepted that a certain fluctuation in the drug level is beneficial in the treatment of various diseases in which circadian rhythm or biorhythm effects may influence the condition being treated. For instance, some physiologically active substances are periodically produced in vivo at certain time intervals, and it may accordingly be desirable to administer such substances in a dosage form which periodically releases the active substance at predetermined time intervals. An appropriate dosage regimen will then lead to a response which is specifically directed to the needs of the particular condition being treated.
Various repeat action formulations are known e.g. Spansuls.RTM., wherein up to four dosage units may be employed in each tablet. Each dosage unit will then be released over predetermined intervals of time depending on the drug properties and manufacturing process. Repeat action formulations may be obtained by coating individual particles or granules of a drug with varying thicknesses of a slowly soluble coating material. The time required for dissolution of the coating is a function of the coating thickness and dissolution rate of the coating substance.
Other drug delivery systems for controlled release of an active substance in discrete pulses are described in. e.g., EP Patent Application Nos. 132,384, 199,362 and 246,819, in GB Patent Application No. 2,189,995 and in JP Patent Application No. 110622/1989. The systems described in these applications include hydrogels, osmotic systems, liposomes and multilayer tablets. Release of the active substance is essentially based on diffusion of the substance through the formulation or on differences in osmotic pressure between an internal layer of the preparation and the surrounding medium.
These pulsatile release formulations have several drawbacks. For example, a strictly controlled release of an active substance from liposomes is difficult to achieve due to, e.g., physical stability problems related to the liposome formulation. Furthermore, the osmotic systems have recently been shown to possess undesirable side effects after oral administration to humans.